Alzheimer's Disease-Related Dementias (ADRD) is a group of progressive neurodegenerative disorders with mid to late life onset such as FTLD-TDP or mixed etiology dementias (MED) including Alzheimer's disease (AD) with TDP-43 pathology. Human studies support the idea that loss of TDP-43 splicing repression underlies neuron loss in these disorders. We recently established that splicing repression is a major function of TDP-43 and validated TDP-43 repression as a promising therapeutic target for FTLD-TDP. By employing a comprehensive set of molecular, pathological, neuronal circuit and behavioral/cognitive approaches, we will functionally validate this type of AAV gene therapeutic strategy to complement TDP-43 repression using both in vivo mouse models and in vitro human iPSC derived neurons in the UG3 phase of the application. Upon meeting the Milestones for transition from UG3 to UH3 phase, we will determine: 1) the optimal dose of AAV gene expression the TDP-43 related repressor required to attenuate neuron loss while limiting any untoward side effects associated with long term exposure of this gene product; 2) the benefit of this AAV gene therapeutic strategy using our mouse model lacking TDP-43 in forebrain neurons in terms of attenuation of altered neuronal circuits, cognitive and behavioural deficits, and neurodegeneration; and 3) ability of AAV gene therapy to restore TDP-43 repression in cortical neurons derived from human iPSCs. Functional validation of TDP-43 repression will address a great unmet need for this type of ADRD.